DE69517201T2 - METHOD FOR THE PRODUCTION OF 2- (2-HYDROXYMETHYLPHENYL) ACETAMIDE DERIVATIVES AND INTERMEDIATE PRODUCTS FOR THE PRODUCTION - Google Patents

Abstract

A process for producing a compound of the formula (I): <CHEM> wherein R<1> and R<2> are the same or different and are hydrogen or alkyl, and R is hydrogen or alkyl, which comprises removing the protective group (P) of hydroxyl of a compound of the formula (II): <CHEM> wherein P is a protective group of hydroxyl, SIMILAR indicates an E-isomer, Z-isomer or a mixture thereof, and the other symbols are as defined above; and an intermediate for the production of the compound of the formula (I).

Description

Process for the preparation of 2-(2-hydroxymethylphenyl)acetamide derivatives and Intermediates for the preparation

The present invention relates to a process for preparing a 2-(2-hydroxymethylphenyl)acetamide derivative, in particular a 2-(2-hydroxymethylphenyl)-2-alkoxy- (or -hydroxy-)iminoacetamide, which is an intermediate in the preparation of alkoxyiminoacetamide compounds useful as agricultural fungicides. The present invention also relates to an intermediate in the preparation of the 2-(2-hydroxymethylphenyl)acetamide derivative.

BACKGROUND OF THE INVENTION

A 2-(2-hydroxymethylphenyl)-2-alkoxy-(or -hydroxy-)iminoacetamide is an important intermediate in the preparation of alkoxyiminoacetamide derivatives useful as agricultural fungicides (see JP-A 3-246268, JP-A 4-182461). The following methods for preparing the intermediate are known: the method which comprises reacting a 2-(2-halomethylphenyl)-2-alkoxyiminoacetic acid ester with a metal acetate followed by an amine (JP-A 3-246268), and the method which comprises converting the halomethyl moiety of a 2-(2-halomethylphenyl)-2-alkoxyiminoacetamide into a hydroxymethyl group (JP-A 5-097768).

However, there is still room for improvement in these procedures.

The object of the present invention is to provide an industrially advantageous process for producing a 2-(2-hydroxymethylphenyl)-2-alkoxy-(or -hydroxy-)iminoacetamide.

Another object of the present invention is to provide an intermediate for the preparation of a 2-(2-hydroxymethylphenyl)-2-alkoxy-(or -hydroxy-)iminoacetamide.

DISCLOSURE OF THE INVENTION

The present inventors have intensively researched to solve the above problems. As a result, it was found that a 2-(2-hydroxymethylphenyl)-2-alkoxy-(or -hydroxy)iminoacetamide can be obtained by deprotecting the corresponding compound in which the hydroxyl group of the hydroxymethyl group is protected. Thus, the present invention was completed.

The present invention relates to a process for preparing a compound of formula (1):

in which R¹ and R² are the same or different and represent a hydrogen atom or an alkyl radical and R represents a hydrogen atom or an alkyl radical, the process comprising removing the protective group (P) for the hydroxyl group of a compound of formula (II):

in which P is a protecting group for the hydroxyl group, ~ indicates an E-isomer, Z-isomer or a mixture thereof and the other symbols are as defined above.

In a preferred aspect, the present invention relates to a process for preparing a compound of formula (I-2):

in which R³ is an alkyl group and the other symbols are as defined above, the process comprising removing a protective group (P) for the hydroxyl group of a compound of the formula (II-1):

in which each symbol is as defined above, to give a compound of formula (I-1):

in which each symbol is as defined above, and then alkylating the compound of formula (I-1).

In the present invention, the compound of formula (II) can be obtained by reacting a compound of formula (IV):

in which each symbol is as defined above, with a compound of formula (III):

NH₂OR (III)

where R is as defined above.

The present invention also provides a compound of formula (II'):

in which R¹ and R² are the same or different and represent a hydrogen atom or an alkyl radical, R is a hydrogen atom or an alkyl radical, P² is a trialkylsilyl, triaralkylsilyl, alkyldiarylsilyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or aralkyloxyalkyl radical and indicates an E-isomer, Z-isomer or a mixture thereof; and a compound of formula (IV'):

where each symbol is as defined above (The compounds of formulas (II') and (IV') are included in the above formulas (II) and (IV) respectively).

The alkyl group denoted by R, R, R² and R³ in the above formulas includes, for example, an alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, such as a methyl group, ethyl group, propyl group, isobutyl group, sec-butyl group and t-butyl group. In particular, a methyl group is preferred.

The hydroxyl protecting groups designated P and P2 include, for example, conventional hydroxyl protecting groups such as ether-type and acetal-type protecting groups described in T. W. Green, "Protective Groups in Organic Synthesis" (1981), pp. 1-113, John Wiley &Sons; and C. B. Reese, "Protective Groups in Organic Chemistry" (1973), edited by J. F. McOmie, pp. 95-143, Plenum Press.

The ether type protecting groups include, for example, alkyl (e.g. C1-6 alkyl, preferably C1-4 alkyl groups such as methyl, ethyl, propyl and t-butyl group), alkenyl (e.g. C2-6 alkenyl, preferably C2-4 alkenyl groups such as allyl group), aralkyl (e.g. substituted or unsubstituted C6-10 aryl-C1-4 alkyl groups such as benzyl, p-methoxybenzyl and triphenylmethyl group), trialkylsilyl (e.g. Tri(C₁₋₆alkyl)silyl radicals, such as triisopropylsilyl and t-butyldimethylsilyl), alkyldiarylsilyl (e.g. (C₁₋₆alkyl)di(C₆₋₁₀aryl)silyl radicals, such as t-butyldiphenylsilyl) and triaralkylsilyl radicals (e.g. tribenzylsilyl).

The acetal type protecting groups include, for example, alkoxyalkyl (e.g. C1-4alkoxyC1-4alkyl groups such as methoxymethyl, 1-ethoxyethyl and 1-methyl-1-methoxyethyl group), alkoxyalkoxyalkyl (e.g. C1-4alkoxyC1-4alkoxyC1-4alkyl groups such as methoxyethoxymethyl group), alkylthioalkyl (e.g. C1-4alkylthioC1-4alkyl groups such as methylthiomethyl group), tetrahydropyranyl (e.g. tetrahydropyran-2-yl or 4- methoxytetrahydropyran-4-yl group), tetrahydrothiopyranyl (e.g. a tetrahydrothiopyran-2-yl group), tetrahydrofuranyl (e.g. a tetrahydrofuran-2-yl group), tetrahydrothiofuranyl (e.g. a tetrahydrothiofuran-2-yl group) or aralkyloxyalkyl radicals (e.g. a benzyloxymethyl group).

Preferably, the protecting groups are removable by treatment with an acid, in particular removable by treatment with an acid and under the conditions for the synthesis of a Grignard reagent (e.g. the compound described below (VIII)) or stable under basic conditions. Preferred examples of the protecting groups include aralkyl (e.g. a triphenylmethyl group), trialkylsilyl (e.g. a t-butyldimethylsilyl or triisopropylsilyl group), triaralkylsilyl (e.g. a tribenzylsilyl group), alkoxyalkyl (e.g. a methoxymethyl, 1-ethoxyethyl or 1-methyl-1-methoxyethyl group), tetrahydropyranyl (e.g. a tetrahydropyran-2-yl group), tetrahydrothiopyranyl (e.g. a tetrahydrothiopyran-2-yl group), tetrahydrofuranyl (e.g. a tetrahydrofuran-2-yl group) and tetrahydrothiofuranyl (e.g. a tetrahydrothiofuran-2-yl group). In particular, tetrahydropyran-2-yl, 1-ethoxyethyl and tetrahydrofuran-2-yl groups are preferred.

The compounds of formulas (II) and (II-1) and (II-2) described below exist as E or Z isomers. These compounds include E or Z isomers and mixtures thereof unless otherwise stated. In the above formulas, this is indicated by the wavy line.

The compounds of formulas (I), (I-1), (I-2) and (II-1) may exist in the form of salts. Examples of the salts include alkali metal salts (e.g. sodium salts, potassium salts or lithium salts).

Preferred examples of the compound of formula (I) include the compound of formula (I) in which R is a hydrogen atom or a methyl group, and R¹ and R² are hydrogen atoms; and the compound of formula (I) in which R is a hydrogen atom or a methyl group, and any one of R¹ and R² is a hydrogen atom and the other is a methyl group.

Preferred embodiments of the method according to the invention are as follows.

The desired compound of formula (I) (hereinafter sometimes abbreviated as compound (I); the other compounds are also abbreviated in the same manner) consists of the compound (I-1) in which R is a hydrogen atom and the compound (I-2) in which R is an alkyl group. The compound (I-1) can be prepared according to Scheme 1 and the compound (I-2) can be prepared according to Scheme 3 or 4. Scheme 1

where each symbol is as defined above.

That is, the compound (I-1) can be obtained by replacing the protecting group (P) for the hydroxyl group of the compound (II-1) is removed.

In this reaction, the protective group for the hydroxyl group is removed and isomerization to the E isomer occurs at the same time. Therefore, no separate isomerization step to the E isomer is required and the compound (I-1) can be obtained in high yield and purity.

This reaction can be carried out using conventional methods for deprotecting a protected hydroxyl group, such as those described in T. W. Green, "Protective Groups in Organic Synthesis" (1981), pp. 1-113, John Wiley &Sons; and C. B. Reese, "Protective Groups in Organic Chemistry" (1973), edited by J. F. McOmie, pp. 95-143, Plenum Press.

For example, when the protecting group for the hydroxyl group is an alkyl (e.g. a t-butyl group), alkenyl (e.g. an allyl group), aralkyl (e.g. a triphenylmethyl group), trialkylsilyl (e.g. a t-butyldimethylsilyl or triisopropylsilyl group), alkyldiarylsilyl (e.g. a t-butyldiphenylsilyl group), triaralkylsilyl (e.g. a tribenzylsilyl group), alkoxyalkyl (e.g. a methoxymethyl, 1-ethoxyethyl or 1-methyl-1-methoxyethyl group), alkoxyalkoxyalkyl (e.g. a methoxyethoxymethyl group), alkylthioalkyl (e.g. a methylthiomethyl group), tetrahydropyranyl (e.g. a tetrahydropyran-2-yl or 4-methoxytetrahydropyran-4-yl group), tetrahydrothiopyranyl (e.g. a tetrahydrothiopyran-2-yl group), tetrahydrofuranyl (e.g. a tetrahydrofuran-2-yl group); tetrahydrothiofuranyl (e.g. a tetrahydrothiofuran-2-yl group) or aralkyloxyalkyl (e.g. a benzyloxymethyl group), the deprotection can be carried out by treating compound (II-1) with an acid.

The acids that can generally be used include, for example, inorganic acids such as hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid), hydrogen halides (e.g. hydrogen chloride, hydrogen bromide or hydrogen iodide), boric acid, phosphoric acid or sulfuric acid; sulfonic acids (e.g. aliphatic sulfonic acids such as trifluoromethanesulfonic acid and aromatic sulfonic acids such as toluenesulfonic acid), carboxylic acids (e.g. acetic acid or trifluoroacetic acid), silica gel, Lewis acids [e.g. aluminum halides (e.g. aluminum chloride), zinc chloride or titanium tetrachloride]. One or more suitable acids can be selected from these acids.

The amount of acid to be used is a trace amount up to 1 equivalent. In another embodiment, carboxylic acids can be used as solvents.

The solvents to be used include, for example, hydrocarbons (e.g. benzene, toluene or xylene), halogenated hydrocarbons (e.g. dichloromethane or 1,2-dichloroethane), ethers (e.g. tetrahydrofuran or dioxane), alcohols (e.g. methanol or ethanol), nitriles (e.g. acetonitrile), water and solvent mixtures thereof. The reaction temperature is -80 to 150ºC, preferably -10 to 80ºC. The reaction time is 1 minute to 3 hours, preferably 5 minutes to 1 hour.

When the protecting group is a substituted silyl group, the protecting group can also be removed under basic conditions (e.g. sodium hydroxide/hydrous ethanol) or in the presence of fluoride anions (e.g. n-Bu4N+F- or C5H5N+HF-).

Since the compound (I-1) thus obtained has a high E-isomer/Z-isomer ratio in which the preferred E-isomer predominates, it can be used in the next step as the reaction mixture or crude product or, if necessary, after purification by conventional methods (e.g., column chromatography or recrystallization).

The compound (II-1) which can be used as the starting material for this reaction can preferably be prepared according to Scheme 2 below. Scheme 2

where each symbol is as defined above.

That is, the compound (II-1) can be prepared by reacting the compound (IV) with hydroxylamine and/or its salt in a suitable solvent.

The amount of hydroxylamine to be used is 1 to 4 equivalents, preferably 1 to 3 equivalents, based on the compound (IV).

The hydroxylamine salts include, for example, salts with mineral acid such as hydrochloric acid or sulfuric acid. When the hydroxylamine salts are used, the salts are neutralized with a base so that the protective group for the hydroxyl group is not removed. The bases that can be used include, for example, metal hydroxides (e.g., sodium hydroxide or potassium hydroxide), metal carbonates (e.g., sodium carbonate or potassium carbonate), metal alkoxides (e.g., sodium methoxide or sodium ethoxide) and amines (e.g., pyridine). The amount of base to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, based on the hydroxylamine salt.

The solvents that can be used include, for example, hydrocarbons (e.g. benzene, toluene or xylene), halogenated hydrocarbons (e.g. chloroform or 1,2-dichloroethane), ethers (e.g. tetrahydrofuran or dioxane), alcohols (e.g. methanol, ethanol, n-propanol or isopropanol) or water and solvent mixtures thereof.

The reaction temperature is 0 to 150ºC, preferably 20 to 100ºC. The reaction The duration of the treatment is usually about 15 minutes to 24 hours.

The compound (II-1) thus obtained can be used in the next step as the reaction mixture or the crude product or after purification by conventional methods (e.g. column chromatography or recrystallization).

The compound (I-2) can be prepared according to Scheme 3 below. Scheme 3

where each symbol is as defined above.

That is, the compound (I-2) can be prepared by reacting the compound (I-1) with an alkylating agent in the presence of a base in an appropriate solvent to alkylate the compound (I-1).

The alkylating agents include, for example, dialkyl sulfates (e.g., di(C1-6 alkyl) sulfates such as dimethyl sulfate or diethyl sulfate), alkyl halides (e.g., C1-6 alkyl halides such as methyl chloride, methyl bromide or methyl iodide). The amount of the alkylating agent to be used is 1 to 10 moles, preferably 1 to 1.5 moles per mole of the compound (I-1).

The solvents include, for example, ketones (e.g. acetone or ethyl methyl ketone), ethers (e.g. tetrahydrofuran or dioxane), hydrocarbons (e.g. toluene, benzene, hexane or cyclohexane), halogenated hydrocarbons (e.g. dichloromethane or 1,2- dichloroethane), alcohols (e.g. methanol or ethanol) or water and solvent mixtures thereof.

The bases include, for example, metal carbonates (e.g., sodium carbonate or potassium carbonate), metal hydroxides (e.g., sodium hydroxide, potassium hydroxide or lithium hydroxide), metal hydrides (e.g., sodium hydride or lithium hydride). The amount of the base to be used is 1 to 10 moles, preferably 1 to 2 moles per mole of the compound (I-1).

If necessary, this reaction can be carried out in the presence of a phase transfer catalyst. The phase transfer catalysts include, for example, quaternary ammonium salts [e.g., tetraalkylammonium halides (e.g., tetrabutylammonium chloride or tetrabutylammonium bromide), tetraalkylammonium hydrogensulfates (e.g., tetrabutylammonium hydrogensulfate)], amines (e.g., tris(3,6-dioxaheptyl)amine). The amount of the phase transfer catalyst to be used is 0.01 to 1 mol, preferably 0.01 to 0.2 Moles per mole of compound (I-1).

The reaction temperature is normally -20 to 100ºC, preferably 0 to 50ºC, and the reaction time is normally 1 to 24 hours.

The compound (I-2) thus obtained can be used in the next step as the reaction mixture or crude product or after purification by conventional methods (e.g. column chromatography or recrystallization).

Alternatively, the compound (I-2) can be prepared according to Scheme 4 below. Scheme 4

where each symbol is as defined above.

That is, the compound (I-2) can be prepared by removing the protecting group (P) for the hydroxyl group of the compound (II-2).

In this reaction, the protective group for the hydroxyl group is removed and simultaneously the isomerization to the E-isomer takes place. Therefore, no separate isomerization step to the E-isomer is required and the compound (I-2) can be obtained in high yield and purity.

This reaction can be carried out under the same reaction conditions as those of the reaction in Scheme 1.

The compound (I-2) thus obtained can be used in the next step as the reaction mixture or crude product or after purification by conventional methods (e.g. column chromatography or recrystallization).

The compound (II-2) which can be used as the starting material for the reaction of Scheme 4 can preferably be prepared according to Scheme 5 below. Scheme 5

where each symbol is as defined above.

That is, the compound (II-2) can be prepared by reacting the compound (IV) with the compound (III-1) and/or its salts. The salts of the compound (III-1) include the same salts as those of the hydroxylamine of Scheme 2.

This reaction can be carried out under the same reaction conditions as those of the reaction in Scheme 2.

The compound (II-2) thus obtained can be used in the next step as the reaction mixture or crude product or after purification by conventional methods (e.g. column chromatography or recrystallization).

The compound (IV) which can be used as the starting material in Scheme 2 or 5 can preferably be prepared according to Scheme 6 below. Scheme 6

where L is a halogen atom or an alkoxy group and the other symbols are as defined above.

That is, the compound (IV) can be prepared by reacting the compound (VI) with the compound (V).

The halogen atoms designated L include fluorine, chlorine, bromine and iodine. Chlorine and bromine are particularly preferred.

The alkoxy group denoted by L includes an alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methoxy, ethoxy or propoxy group.

The compound (V) is added dropwise to the compound (VI) without the compound (V) is diluted with a solvent or after it has been diluted with a suitable solvent. In another embodiment, the gaseous compound (V) is introduced into the compound (VI).

The amount of compound (V) is 1 to 10 equivalents, preferably 1 to 5 equivalents, based on compound (VI). When compound (VI) is an α-keto acid halide, the amount of compound (V) is preferably 2 to 6 equivalents, based on compound (VI).

When an isolated α-keto acid ester is used as the compound (VI), it is diluted with a suitable solvent. The solvents include, for example, hydrocarbons (e.g. benzene, toluene or xylene), halogenated hydrocarbons (e.g. dichloromethane or 1,2-dichloroethane), ethers (e.g. tetrahydrofuran or dioxane), alcohols (e.g. methanol or ethanol) or water and solvent mixtures thereof.

The compound (V) is added dropwise or introduced at -75 to 50°C, preferably -60 to 30°C, over 5 minutes to 2 hours, preferably 15 minutes to 1 hour. Then the reaction is carried out at -50 to 100°C, preferably -30 to 60°C, for 1 minute to 5 hours, preferably 10 minutes to 2 hours, to obtain compound (IV).

The compound (IV) thus obtained can be used in the next step as the reaction mixture or crude product or after purification by conventional methods (e.g. column chromatography or recrystallization).

The compound (VI) which can be used as the starting material for the reaction of Scheme 6 can preferably be prepared according to Scheme 7 below. Scheme 7

where X is a halogen atom and the other symbols are as defined above.

That is, the compound (VI) can be prepared by reacting the compound (VIII) with the compound (VII).

The halogen atoms denoted by X include fluorine, chlorine, bromine and iodine. In particular, chlorine, bromine or iodine are preferred.

Normally, a solution of the compound (VIII) is added dropwise to a solution of the compound (VII) in a suitable solvent. The amount of the compound (VII) to be used is 1 to 4 equivalents, preferably 1 to 2 equivalents, based on the compound (VIII).

The addition is carried out at -100 to 50°C, preferably -70 to 30°C, within 5 minutes to 2 hours, preferably 15 minutes to 1 hour. Then the reaction is carried out at -100 to 50°C, preferably -80 to 30°C, within 5 minutes to 2 hours, preferably 15 minutes to 1 hour.

The solvents include ethers such as THF, diethyl ether or dibutyl ether, and hydrocarbons such as toluene.

Examples of the compound (VII) include oxalyl halides such as oxalyl chloride or oxalyl bromide, oxalic acid esters such as dimethyl oxalate or diethyl oxalate, alkyl oxalyl chlorides such as methyl oxalyl chloride or ethyl oxalyl chloride.

Alternatively, the compound (VII) which is not diluted or diluted with a suitable solvent may be added dropwise to the compound (VIII) for reaction. The solvent and reaction conditions may be the same as those described above.

When the compound (VI) thus obtained is an α-keto acid halide, it can be used as the reaction mixture in the next step. When it is an α-keto acid ester, it can be used as the reaction mixture or crude product in the next step or after purification by conventional methods (e.g. column chromatography or recrystallization).

In another embodiment, when the compound (VI) is an α-keto acid ester, the compound (VIII) in which MgX has been replaced by Li is used as the starting material and reacted with the compound (VII).

The compound of formula (VI'):

in which each symbol is as defined above and which is included in the above compound (VI) is a novel compound and is included in the present invention.

L is preferably an alkoxy radical.

The compound (VW) which can be used as the starting material in the reaction of Scheme 7 can preferably be prepared according to Scheme 8 below. Scheme 8

where each symbol is as defined above.

That is, the compound (VIII) can be prepared by reacting the compound (IX) with magnesium in a suitable solvent.

Normally, magnesium is reacted with the compound (IX) in an amount of 1 to 4 equivalents, preferably 1 to 2 equivalents, based on the compound (IX).

The solvents to be used include ethers such as dry THF, diethyl ether or dibutyl ether. These solvents can be used alone or as mixtures with other solvents such as hydrocarbons (e.g. toluene) or amines (e.g. triethylamine).

The reaction temperature is room temperature to 150ºC, preferably 40 to 100ºC. The reaction time is 10 minutes to 48 hours, preferably 30 minutes to 6 hours.

If necessary, a small amount of iodine, dibromoethane or ethyl bromide is used as an activating agent for the reaction. The amount of activating agent is 0.001 to 0.4 equivalents, preferably 0.005 to 0.2 equivalents.

The compound (VIII) in which MgX is replaced by Li can be prepared by reacting the compound (DC) with lithium metal or an alkyllithium compound (e.g. n-butyllithium).

The compound (VIII) thus obtained can be used in the next step as the reaction mixture or crude product.

The compound (DC), which can be used as the starting material in the reaction of Scheme 8, can preferably be prepared according to Scheme 9. Scheme 9

where each symbol is as defined above.

That is, the compound (IX) can be prepared by protecting the hydroxyl group of the commercially available compound (X) with an appropriate protecting group.

The hydroxyl group can be protected using conventional hydroxyl protection methods, such as those described in T. W. Green, "Protective Groups in Organic Synthesis" (1981), pp. 1-113, John Wiley &Sons; and C. B. Reese, "Protective Groups in Organic Chemistry" (1973), edited by J. F. McOmie, pp. 95-143, Plenum Press.

For example, the compound (IX) protected with a tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl or 1-methyl- 1-methoxyethyl radical can be prepared by reacting the corresponding olefins with the compound (X) in the presence of an acid catalyst in a suitable solvent or in the absence of a solvent.

The corresponding olefins are 3,4-dihydro-2H-pyran, 2,3-dihydro-4H-thiyne, dihydrofuran, dihydrothiofuran, ethyl vinyl ether and 2-methoxypropene, respectively. These compounds are commercially available or can be prepared using known methods.

The amount of olefin to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, based on the compound (X).

The acid catalysts include, for example, hydrogen chloride, phosphorus oxychloride, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, montmorillonite, bistrimethyl sulfate, acetic acid, pyridinium polyvinyl-p-toluenesulfonate, trifluoroacetic acid, boron trifluoride etherate (BF3·OEt2) and acidic ion exchange resins.

If the solvent is used, a non-alcoholic solvent may be used. Examples of the solvents include hydrocarbons (e.g., benzene, toluene or xylene), halogenated hydrocarbons (e.g., chloroform or dichloromethane), ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), esters (e.g., ethyl acetate) or N,N-dimethylformamide and mixtures thereof.

The reaction temperature is -30 to 100ºC, preferably 0 to 60ºC.

The reaction time is usually about 15 minutes to 24 hours.

The silyl ether compound (IX) can be obtained by reacting the compound (X) with a suitable silylating agent. Generally, chlorosilane is used as the silylating agent and reacted with the compound (X) in the presence of a base in a suitable solvent.

The chlorosilane is commercially available or can be produced using known processes.

The amount of chlorosilane to be used is 1 to 5 equivalents, preferably 1 to 2 equivalents, based on the compound (X). The bases to be used include organic bases (e.g. N,N-dimethylaniline, pyridine, triethylamine or imidazole), metal carbonates (e.g. sodium carbonate or potassium carbonate), metal hydrides (e.g. sodium hydride or potassium hydride) or metal bicarbonates (e.g. sodium bicarbonate or potassium bicarbonate). The amount of base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.

The solvents to be used include hydrocarbons (e.g. hexane, benzene, toluene or xylene), halogenated hydrocarbons (e.g. chloroform or dichloromethane), ethers (e.g. diethyl ether, tetrahydrofuran or dioxane), ketones (e.g. acetone or methyl ethyl ketone), nitriles (e.g. acetonitrile), N,N-dimethylformamide or dimethyl sulfoxide and solvent mixtures thereof.

The reaction temperature is -20 to 100ºC, preferably 0 to 60ºC.

The reaction time is 5 minutes to 30 hours, preferably 30 minutes to 15 hours.

The compound (lix) protected with a methoxymethyl or triphenylmethyl group and the above compound (IX) protected with a tetrahydrofuranyl or 1-ethoxyethyl group can be obtained by reacting the corresponding halides with the compound (X) in the presence of a base.

The corresponding halides are halomethyl methyl ether, triphenylmethyl halides, 2-halotetrahydrofurans and 1-haloethyl ether. These compounds are commercially available or can be prepared using known methods.

Chlorides or bromides can be used as the halides.

The amount of halide to be used, the kinds of base and solvent and the reaction conditions are the same as those in the reaction between the above chlorosilane and the compound (X).

The above compound (IX) protected with a methoxymethyl group can also be obtained by reacting the compound (X) with dimethoxymethane in the presence of a suitable catalyst (e.g. phosphorus pentoxide).

The solvents to be used and the reaction conditions are the same as those in the above reaction between the olefin and the compound (X).

The compound (IX) thus obtained can be used in the next step as the crude product or after purification by conventional methods (e.g. column chromatography or recrystallization). installation).

The compound (I-2) obtained in the reactions of Schemes 3 and 4 can be conveniently converted into the alkoxyiminoacetamide compound (XI) which has effective antifungal activity and is useful as an agricultural fungicide, for example, according to Scheme 10 below (JP-A 3-246268, JP-A 4-182461). Thus, the compound (I-2) is important as an intermediate in the preparation. Scheme 10

where A is an optionally substituted phenyl radical or an optionally substituted heterocyclic radical, X' is defined as X and the other symbols are as defined above.

That is, compound (I-2) is reacted with compound (XII) according to JP-A 3-246268 or JP-A 4-182461 to obtain compound (XI).

The phenyl group denoted by A includes a substituted or unsubstituted phenyl group. The heterocyclic groups denoted by A include, for example, heterocyclic groups containing at least one heteroatom selected from nitrogen, oxygen and sulfur which constitutes the ring, such as a pyridyl, pyrimidinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl or quinolyl group. When these groups are substituted, preferred examples of the substituent include methyl, trifluoromethyl, trichloromethyl, fluoro, chloro or methoxy group.

EXAMPLES

The following examples and reference examples further illustrate the present invention in detail, but should not be construed as limiting the scope of the invention.

example 1 Preparation of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene

Pyridinium p-toluenesulfonate (0.50 g, 0.002 mol) was added under ice cooling to a mixed solution of 2-bromobenzyl alcohol (18.70 g, 0.1 mol), dichloromethane (150 ml) and Ethyl vinyl ether (14.42 g, 0.2 mol) was added and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, a half-saturated aqueous sodium bicarbonate solution (300 ml) was added and the mixture was extracted twice with dichloromethane (100 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (25.44 g, yield: 98.2%) as a colorless oil.

1 H-NMR (CDCl3 ) ? ppm: 1.22 (3H, t, J=7.3); 1.41 (3H, t, J=5.5); 3.49 - 3.77 (2H, m); 4.59 (1H, d, J=12.8); 4.70, (1H, d, J=12.8); 4.87 (1H, q, J=5.5); 7.11 - 7.55 (4H, m).

Example 2 Preparation of 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene

Pyridinium p-toluenesulfonate (0.30 g, 0.0012 mol) was added to a solution of 2-bromobenzyl alcohol (25 g, 0.134 mol) in dichloromethane (100 mL), and the mixture was stirred at room temperature. To this mixture was added 3,4-dihydro-2H-pyran (16.86 g, 0.20 mol). After the resulting mixture was stirred at room temperature for 2 hours, a saturated aqueous sodium bicarbonate solution (200 mL) was added. The mixture was extracted with dichloromethane (200 mL). After the mixture was dried over anhydrous magnesium sulfate, the solvent was evaporated to give the desired compound 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (36.00 g, yield: 99.3%) as an oil.

1 H-NMR (CDCl3 ) ? ppm: 1.45 - 1.80 (6H, m); 3.45 - 3.55 (1H, m); 3.80 - 3.90 (1H, m) ; 4.52 (1H, d, J=15.0); 4.80 (1H, m); 4.90 (1H, d, J=15.0); 7.16 (1H, t, J=7.3); 7.31 (1H, t, J=7.3); 7.51 (1H, d, J=7.3); 7.54 (1H, d, J=7.3).

Example 3 Preparation of ethyl 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-oxoacetate

A mixed solution of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (3.11 g, 0.012 mol) and dry THF (10 ml) was added dropwise to a solution prepared by adding dry THF (2 ml) and ethyl bromide (0.2 ml) to magnesium (0.44 g, 0.018 mol) in a nitrogen stream over 25 minutes at 50 to 60 °C. After the addition was complete, the mixture was stirred at 50 to 60 °C for 1 hour and cooled to room temperature. After cooling, the mixture was added dropwise to a mixed solution of ethyl oxalate (2.63 g, 0.018 mol) and dry THF (30 ml) over 15 minutes below -50 °C. Then, the mixture was stirred at -50 to -60 °C for 1 hour. After the reaction was complete, water (200 ml) was added and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give ethyl 2-[2-{(1-ethoxyethyl)- oxymethyl}phenyl]-2-oxoacetate (2.30 g, yield: 68.4%) was obtained as a colorless oil.

1 H-NMR (CDCl3 ) ? ppm: 1.19 (3H, t, J=7.3); 1.36 (3H, d, J=5.5); 1.41 (3H, t, J=7.3); 3.47 - 3.68 (2H, m); 4.42 (2H, q, J=7.3); 4.78-5.01 (3H, m); 7.32 - 7.71 (4H, m).

Example 4 Preparation of ethyl 2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetate

Magnesium (2.67 g, 0.11 mol) and bromoethane (0.2 mL) were added to a mixed solution of 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (27.11 g, 0.10 mol) and THF (50 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour to prepare a Grignard reagent. The Grignard reagent was added dropwise to a mixed solution of diethyl oxalate (29.23 g, 0.20 mol) and THF (100 mL) cooled to -78 °C. The mixture was stirred at -78 °C for 1 hour, water (150 mL) was added, and the mixture was extracted with ether (200 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give ethyl 2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetate (22.60 g, yield: 77.3%) as a colorless oil.

1 H-NMR (CDCl3 ) ? ppm: 1.38 (3H, t, J=7.0); 1.40 - 1.85 (6H, m); 3.50 - 3.60 (1H, m); 3.80 - 3.90 (1H, m); 4.32 - 4.40 (2H, m); 4.69 (1H, m); 4.85 (1H, d, J=14.6); 5.09 (1H, d, J=14.6); 7.43 (1H, t, J=7.3); 7.58 - 7.70 (3H, m).

Example 5 Preparation of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide

A 40% methylamine-methanol solution (1.63 g, 0.021 mol) was added to a mixed solution of ethyl 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-oxoacetate (1.96 g, 0.007 mol) and THF (7 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (100 ml) was added and the mixture was extracted twice with dichloromethane (80 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (1.35 g, yield: 72.7%) as a colorless oil.

1 H-NMR (CDCl3 ) ? ppm: 1.17 (3H, t, J=7.3); 1.29 (3H, d, J=4.9); 2.96 (3H, d, J=5.5); 3.41 - 3.63 (2H, m); 4.70 - 4.92 (3H, m); 7.04 (1H, brs); 7.33 - 7.84 (4H, m).

Example 6 Preparation of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide

A mixed solution of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (7.77 g, 0.03 mol) and dry THF (27 ml) was heated to 50-60°C for 30 minutes to give solution prepared by adding dry THF (3 ml) and ethyl bromide (0.2 ml) to magnesium (1.09 g, 0.045 mol) in a nitrogen stream. After the addition was complete, the mixture was stirred at 50-60 °C for 1 hour and cooled to room temperature. After cooling, the mixture was added dropwise to a mixed solution of ethyl oxalate (6.58 g, 0.045 mol) and dry THF (50 ml) below -60 °C over 15 minutes. Then, the mixture was stirred at -60-70 °C for 1 hour. A 40% methylamine-methanol solution (11.65 g, 0.15 mol) was added to the reaction mixture and the temperature of the mixture was raised from -50 °C to room temperature over 1 hour. After the reaction was complete, water (500 mL) was added and the mixture was extracted with ether (300 mL) followed by dichloromethane (300 mL). The extract was combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (3.83 g, yield: 48.1%) as a colorless oil.

Example 7 Preparation of N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide

A 40% methylamine-methanol solution (2.65 g, 0.0341 mol) was added to a mixed solution of ethyl 2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetate (2.00 g, 0.0068 mol) and methanol (20 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (1.30 g, yield: 69.0%) as a colorless oil.

1 H-NMR (CDCl3 ) ? ppm: 1.49 - 1.80 (6H, m); 2.96 (3H, d, J=4.9); 3.47 - 3.52 (1H, m); 3.77 - 3.86 (1H, m); 4.62 (1H, t, J=3.1); 4.76 (1H, d, J=13.4); 4.98 (1H, d, J=13.4); 7.06 (1H, brs); 7.34 - 7.80 (4H, m).

Example 8 Preparation of N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide

A mixed solution of 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (2.71 g, 0.01 mol) and dry THF (8 ml) was added dropwise over 20 minutes at 50-60°C to a solution prepared by adding dry THF (2 ml) and ethyl bromide (0.1 ml) to magnesium (0.36 g, 0.015 mol) under nitrogen flow. After the addition was complete, the mixture was stirred at 50-60°C for 1 hour and concentrated to zirconia. mer temperature. After cooling, the mixture was added dropwise to a mixed solution of oxalyl chloride (1.90 g, 0.015 mol) and dry THF (30 ml) over 15 minutes below -50 °C. Then, the mixture was stirred at -60 to -70 °C for 40 minutes. A 40% methylamine-methanol solution (4.66 g, 0.06 mol) was added to the reaction mixture, and the mixture was stirred at -20 to -10 °C for 30 minutes. After the reaction was complete, water (150 ml) was added, and the mixture was extracted with ether (150 ml). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (1.18 g, yield: 42.5%) as a colorless oil.

Example 9 Preparation of N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide

A mixed solution of 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (2.71 g, 0.01 mol) and dry THF (8 ml) was added dropwise over 20 minutes at 50-60°C to a solution prepared by adding dry THF (2 ml) and ethyl bromide (0.1 ml) to magnesium (0.36 g, 0.015 mol) in a nitrogen stream. After the addition was complete, the mixture was stirred for 1 hour at 50-60°C and cooled to room temperature. After cooling, the mixture was added dropwise over 10 minutes below -60°C to a mixed solution of ethyl oxalate (2.19 g, 0.015 mol) and dry THF (20 ml). Then, the mixture was stirred at -60 to -70°C for 1 hour. A 40% methylamine-methanol solution (3.88 g, 0.05 mol) was added to the reaction mixture, and the temperature of the mixture was raised from -50°C to room temperature over 1 hour. After the reaction was complete, water (200 ml) was added and the mixture was extracted with ether (200 ml). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (1.21 g, yield: 43.6%) as a colorless oil.

Example 10 Preparation of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-hydroxyimino-N-methylacetamide

Methanol (4 mL) and 50% aqueous hydroxylamine solution (0.4 g, 0.006 mol) were added to give 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (0.53 g, 0.002 mol) The mixture was stirred under reflux for 5 hours. After the reaction was complete, water (100 ml) was added, and the mixture was extracted twice with dichloromethane (50 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-hydroxyimino-N-methylacetamide (isomer A: 0.21 g (yield: 37.5%), colorless oil; isomer B: 0.14 g (yield: 25.0%), colorless crystals). Isomer A:

1 H-NMR (CDCl3 ) ? ppm: 1.67 (3H, t, J=7.3); 1.30 (3H, d, J=5.5); 2.82 (3H, d, J=5.5); 3.42 - 3.63 (2H, m); 4.54 (1H, d, J=11.6); 4.66 (1H, d, J=11.6); 4.73 (1H, q, J=5.5); 6.00 (1H, brs); 7.30 - 7.49 (4H, m).

Isomer B: mp 85-87ºC

1 H-NMR (CDCl3 ) ? ppm: 1.16 (3H, t, J=7.3); 1.28 (3H, d, J=4.9); 2.90 (3H, d, J=4.9); 3.44 - 3.61 (2H, m); 4.44 (1H, d, J=12.8); 4.58 (1H, d, J=12.8); 4.71 (1H, q, J=5.5); 6.72 (1H, brs); 7.18 - 7.51 (4H, m); 8.30 (1 hour, brs).

Example 11 Preparation of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-methoxyimino-N-methylacetamide

Methoxyamine hydrochloride (0.50 g, 0.006 mol) was dissolved in methanol (6 mL), and a 28% sodium methoxide-methanol solution (1.45 g, 0.0075 mol) was added to the solution to obtain a suspension. A mixed solution of 2-[2-{(1- ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (0.80 g, 0.003 mol) and methanol (3 mL) was added to the suspension, and the mixture was stirred under reflux for 1 hour. After the reaction was complete, half-saturated brine (150 mL) was added, and the mixture was extracted twice with dichloromethane (100 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give an E/Z mixture of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]- 2-methoxyimino-N-methylacetamide (0.82 g, yield: 92.8%) as a colorless oil.

1 H-NMR (CDCl3 ) ? ppm: 1.18 (1.20) (3H, t, J=7.3); 1.28 (1.33) (3H, d, J=5.5); 2.87 (2.91) (3H, d, J=4.9); 3.41-6.64 (2H, m); 3.95 (4.00) (3H, s); 4.36 - 4.83 (3H, m); 6.76 (7.01) (1H, brs); 7.14 - 7.49 (4H, m).

Example 12 Preparation of 2-methoxyimino-N-methyl-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide

Methoxyamine hydrochloride (0.33 g, 0.004 mol) was dissolved in methanol (4 ml) and Pyridine (0.47 g, 0.006 mol) was added to the solution. To the mixture was added a mixed solution of N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (0.55 g, 0.002 mol) and methanol (2 ml). The mixture was stirred under reflux for 2 hours. After the completion of the reaction, half-saturated brine (100 ml) was added and the mixture was extracted twice with dichloromethane (80 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give an E/Z mixture of 2-methoxyimino-N-methyl-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (0.37 g, yield: 60.4%) as a colorless oil.

1 H-NMR (CDCl3 ) ? ppm: 1.43 - 1.90 (6H, m); 2.87 (2.91) (3H, d, J=4.9); 3.44 - 3.60 (1H, m); 3.78 - 3.91 (1H, m); 3.94 (4.01) (3H, s); 4.36 - 4.94 (3H, m); 6.75 (7.00) (1H, brs); 7.15 - 7.48 (4H, m).

Example 13 Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide

Hydroxylamine hydrochloride (0.28 g, 0.004 mol) was dissolved in methanol (4 mL), and a 28% sodium methoxide-methanol solution (0.96 g, 0.005 mol) was added, to obtain a suspension. A mixed solution of 2-{2-[(1-ethoxyethyl)oxymethyl]phenyl}-N-methyl-2-oxoacetamide (0.53 g, 0.002 mol) and methanol (2 mL) was added to the suspension. The mixture was stirred under reflux for 2 hours. After the completion of the reaction, half-saturated brine (150 mL) was added and the mixture was extracted twice with dichloromethane (100 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2-[2-(1-ethoxyethyl)oxymethyl]phenyl-2-hydroxyimino-N-methylacetamide as a crude product. Methanol (4 ml) and pyridinium p-toluenesulfonate (0.05 g, 0.0002 mol) were added to the crude product thus obtained, and the mixture was stirred under reflux for 30 minutes. After the reaction was complete, the mixture was concentrated, and acetone (4 ml) was added to the residue. Then, under ice-cooling, potassium carbonate (0.41 g, 0.003 mol) and dimethyl sulfate (0.30 g, 0.0024 mol) were added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.24 g, yield: 54.0%, E 100%) as a colorless oil. A portion of it was recrystallized from ethyl acetate/n-hexane to give crystals (mp 107-108 °C).

1 H-NMR (CDCl3 ) ? ppm: 2.95 (3H, d, J=4.9); 3.13 (1H, t, J=6.1); 3.96 (1H, s); 4.40 (2H, d, J=6.1); 6.95 (1H, brs); 7.11 - 7.55 (4H, m).

Example 14 Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide

Methanol (4 mL) and pyridinium p-toluenesulfonate (0.04 g, 0.00017 mol) were added to an E/Z mixture of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-methoxyimino-N-methylacetamide (0.50 g, 0.0017 mol), and the mixture was stirred under reflux for 2 h. After the reaction was complete, half-saturated brine (100 mL) was added, and the mixture was extracted twice with dichloromethane (50 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.34 g, yield: 90.0%, E/Z = 96/4) as a colorless oil.

Example 15 Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide

Methanol (2 mL) and 36% hydrochloric acid (0.01 g, 0.0001 mol) were added to an E/Z mixture of 2-methoxyimino-N-methyl-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (0.31 g, 0.001 mol), and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, half-saturated brine (80 mL) was added, and the mixture was extracted twice with dichloromethane (50 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.21 g, yield: 94.6%, E/Z = 97/3) as colorless crystals.

Example 16 Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide

Methoxyamine hydrochloride (0.22 g, 0.0026 mol) was dissolved in methanol (2 ml), and a 28% sodium methoxide-methanol solution (0.58 g, 0.003 mol) was added to the solution to obtain a suspension. A mixed solution of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (0.53 g, 0.002 mol) and methanol (2 ml) was added to the suspension. The mixture was stirred under reflux for 3 hours and then cooled to room temperature. After cooling, p-toluenesulfonic acid monohydrate (0.19 g, 0.001 mol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, half-saturated brine (80 ml) was added and the mixture was extracted twice with dichloromethane (50 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-hydroxymethylphenyl)-2-methoxyimino-N- methylacetamide (0.37 g, yield: 83.2%, E/Z = 97/3) was obtained as colorless crystals.

Example 17 Preparation of N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide

Pyridinium p-toluenesulfonate (6.70 g, 0.027 mol) and 3,4-dihydro-2H-pyran (97.6 mL, 1.067 mol) were added to a solution of 2-bromobenzyl alcohol (100.9 g, 0.539 mol) in dichloromethane (500 mL) and the mixture was stirred at room temperature for 70 hours. After the reaction was complete, the mixture was washed twice with water (200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oil (152.11 g).

A mixed solution of the crude 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene thus obtained and dry THF (100 mL) was added dropwise to a solution prepared by adding dry THF (50 mL) and ethyl bromide (1 mL) to magnesium (16.8 g, 0.70 mol) at 50 to 55 °C over 45 minutes under a nitrogen stream. After the addition was complete, dry THF (200 mL) was added. The mixture was stirred at 55 °C for 30 minutes and cooled to room temperature. After cooling, the mixture was added dropwise to a mixed solution of ethyl oxalate (118.6 g, 0.80 mol) and dry THF (400 mL) at -65 to -70 °C over 1 hour, and the resulting mixture was stirred at -78 °C for 1 hour. Water (300 mL) and a saturated aqueous solution of ammonium chloride (80 mL) were added, and the mixture was stirred. Then, the organic phase and the aqueous phase were separated, and the aqueous phase was extracted with ether (500 mL). The organic phase was combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil (214.7 g).

A 40% methylamine-methanol solution (167.4 g, 2.156 mol) was added to a mixed solution of the crude ethyl α-oxo-2-(2-tetrahydropyranyloxymethyl)phenylacetate thus obtained and methanol (100 ml), and the mixture was stirred at room temperature for 40 minutes. After the completion of the reaction, the mixture was concentrated under reduced pressure. Benzene (300 ml) was added to the resulting residue to filter off the insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/hexane) to obtain N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (114.8 g, yield: 76.8%) as an oil.

Example 18 Preparation of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide

A mixed solution of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (25.92 g, 0.1 mol) and dry THF (90 mL) was added dropwise at 50 to 55°C over 40 minutes to a solution prepared by adding dry THF (10 mL) and ethyl bromide (0.2 mL) to magnesium (3.65 g, 0.15 mol) in a nitrogen stream. After the addition was complete, the mixture was stirred at 50 to 55°C for 1 hour and cooled to room temperature. After cooling, the mixture was added dropwise at -70 to -65°C over 1 hour to a mixed solution of ethyl oxalate (21.92 g, 0.15 mol) and dry THF (100 mL). Then, the mixture was stirred at -75 to -70°C for 1 hour. After the reaction was complete, water (200 ml) and a saturated aqueous ammonium chloride solution (100 ml) were slowly added, and the mixture was extracted with ether (300 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in methanol (100 ml), and a 40% aqueous methylamine solution (23.30 g, 0.3 mol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (300 ml) was added, a portion of the methanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (300 ml). The extract was washed with saturated brine (300 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (19.11 g, yield: 72.0%) as a colorless oil.

Example 19 Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide

Methoxyamine hydrochloride (7.52 g, 0.09 mol) was dissolved in methanol (60 ml), and a 28% sodium methoxide-methanol solution (19.68 g, 0.102 mol) was added to the solution under ice-cooling to obtain a suspension. A solution of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (15.92 g, 0.06 mol) in methanol (60 ml) was added to the suspension. The mixture was stirred under reflux for 2 hours. After the completion of the reaction, about half of the methanol was evaporated under reduced pressure, water (400 ml) was added, and the mixture was extracted twice with dichloromethane (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in methanol (30 ml), 36% hydrochloric acid (0.61 g, 0.006 mol) was added under ice-cooling and the mixture was stirred for 0.5 hours. After the reaction was complete, water (370 ml) and saturated sodium bicarbonate (30 ml) were added and the mixture was extracted twice with dichloromethane (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (12.98 g, yield: 97.3%, E/Z = 96/4) as colorless crystals.

Reference example 1 Synthesis of (E)-2-[2-(5-chloro-3-trifluoromethylpyridin-2-yloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide

2-(2-Hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (300 mg) was dissolved in THF (5 mL). 40% sodium hydride (65 mg) was added and the mixture was stirred for 10 minutes. 2,5-Dichloro-3-trifluoromethylpyridine (350 mg) was added and the mixture was stirred at room temperature for 12 hours. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The resulting organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the title compound (398 mg, yield: 74%).

Melting point 105-106ºC

1 H-NMR (CDCl3 ) ? ppm: 2.94 (3H, d, J=5.1Hz); 3.96 (3H, s); 5.23 (2H, s); 6.82 (1H, brs); 7.21 (1H, dd, J=7.3, 1.7 Hz); 7.36 (1H, td, J=7.3, 1.7 Hz); 7.42 (1H, td, J=7.3, 1.7 Hz); 7.58 (1H, dd, J=7.3, 1.7 Hz); 7.81 (1H, dd, J=2.4, 0.7 Hz); 8.16 (1H, dd, J=2.4, 0.7 Hz).

The present invention provides an economically and industrially advantageous process for producing a 2-(2-hydroxymethylphenyl)-2-alkoxy-(or -hydroxy-)iminoacetamide derivative useful as an intermediate in the production of alkoxyiminoacetamide compounds useful as agricultural fungicides, as well as an intermediate used in the process.

The alkoxyiminoacetamide compound useful as an agricultural fungicide can be obtained from compound (I) in a few steps. Since its E-isomer has more effective fungicidal activity than its Z-isomer, it is preferred to obtain compound (I) as an E-isomer. In the process of the present invention, the protecting group for the hydroxyl group is removed and at the same time, isomerization to the E-isomer proceeds. Therefore, this process can provide the E-isomer of compound (I) in a few steps and in high yield and purity without any separate isomerization step to the E-isomer. Thus, this process is highly useful in industrial production.

Claims (16)

1. Process for preparing a compound of formula (I): in which R¹ and R² are the same or different and represent a hydrogen atom or an alkyl radical and R represents a hydrogen atom or an alkyl radical, the process comprising removing the protective group (P) for the hydroxyl group of a compound of formula (II): in which P is a protecting group for the hydroxyl group, ~ indicates an E-isomer, Z-isomer or a mixture thereof and the other symbols are as defined above. 2. Process for preparing a compound of formula (I-2): in which R³ is an alkyl radical and the other symbols are as defined in claim 1 , wherein the process comprises removing the protecting group (P) for the hydroxyl group of a compound of formula (II-1): in which each symbol is as defined in claim 1, thereby obtaining a compound of formula (I-1): in which each symbol is as defined above, and then alkylating the compound of formula (I-1). 3. Process according to claim 1 or 2, wherein the protective group (P) for the hydroxyl group is removed by treatment with an acid. 4. A process according to claim 1 or 2, wherein P is a protecting group that is removable by treatment with an acid. 5. A process according to claim 1 or 2, wherein P is a protecting group which is removable by treatment with an acid and stable under the conditions for the synthesis of a Grignard reagent or under basic conditions. 6. The method according to claim 1 or 2, wherein P is an alkyl, alkenyl, aralkyl, trialkylsilyl, triaralkylsilyl, alkyldiarylsilyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl. or aralkyloxyalkyl radical. 7. The process of claim 6, wherein P is a triphenylmethyl, t-butyldimethylsilyl, tri isopropylsilyl, tribenzylsilyl, methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl or tetrahydrothiofuranyl. 8. The process according to claim 7, wherein P is a 1-ethoxyethyl, tetrahydropyranyl or tetrahydrofuranyl radical. 9. A process according to claim 1, wherein the compound of formula (II) is prepared by reacting a compound of formula (IV): in which each symbol is as defined in claim 1, with a compound of formula (III): NH₂OR (III) in which R is as defined in claim 1. 10. The process according to claim 2, wherein the compound of formula (II-1) is obtained by reacting a compound of formula (IV) with hydroxylamine. 11. A process according to claim 9 or 10, wherein the compound of formula (IV) is prepared by reacting a compound of formula (VI): in which L is a halogen atom or an alkoxy radical and the other symbols are as defined in claim 1, with a compound of formula (V): HNR¹R² (V) in which each symbol is as defined in claim 1. 12. A process according to claim 11, wherein the compound of formula (VI) is prepared by reacting a compound of formula (IX): in which X is a halogen atom and the other symbols are as defined in claim 1, with magnesium to obtain a compound of formula (VIII): in which X is as defined above and the other symbols are as defined in claim 1, and then reacting the compound of formula (VIII) with a compound of formula (VII) is obtained: (COL)₂ (VII) in which L is a halogen atom or an alkoxy radical. 13. Compound of formula (II'): in which R¹ and R² are the same or different and represent a hydrogen atom or an alkyl radical, R is a hydrogen atom or an alkyl radical, P² is a trialkylsilyl, triaralkylsilyl, alkyldiarylsilyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or aralkyloxyalkyl radical and ~ indicates an E-isomer, Z-isomer or a mixture thereof. 14. Compound of formula (IV'): in which each symbol is as defined in claim 13. 15. Compound of formula (VI'): in which L is a halogen atom or an alkoxy group and the other symbols are as defined in claim 13. 16. A compound according to claim 15, wherein L is an alkoxy radical.